Proteins and polypeptides have become increasingly important therapeutic and commercial agents. In most cases, these proteins and polypeptides are produced in cell culture, from cells that have been engineered and/or selected to produce unusually high levels of the particular protein or polypeptide of interest. Control and optimization of cell culture conditions is critically important for successful commercial production of proteins and polypeptides.
Many proteins and polypeptides produced in cell culture are made in a batch or fed-batch process, in which cells are cultured for a period of time, and then the culture is terminated and the produced protein or polypeptide is isolated. Alternatively, proteins or polypeptides can be produced in a perfusion cell culture process in which the culture is not terminated and new nutrients and other components are periodically added to the culture, and during which the expressed protein or polypeptide is harvested periodically. The ultimate amount and quality of protein or polypeptide produced can be dramatically affected by the conditions of the cell culture. For example, traditional batch and fed-batch culture processes often result in production of metabolic waste products that have detrimental effects on cell growth or viability, and on production or stability of the protein or polypeptide of interest. Among these detrimental waste products is the glucose metabolite lactate. Lactate accumulation has been shown to reduce the pH of the cell culture, and is detrimental to both cell viability and productivity (see Gorfien et al., Optimized Nutrient Additives for Fed-Batch Cultures, Biopharm. International, April 2003). While a variety of efforts have been made to improve production of proteins and polypeptides in cell culture processes, there remains a need for additional improvements.
Furthermore, significant effort has been invested in the development of defined media (i.e., media assembled from known individual components and lacking serum or other animal byproducts) for use in culturing cells, particularly mammalian cells. Cell growth characteristics can be very different in defined media as contrasted with serum-derived media. There is a particular need for the development of improved systems for producing proteins and polypeptides by cell culture in defined media, in which the accumulation of detrimental waste products is reduced or eliminated.